We have recently developed the Prediction of MLH1 and MSH2 mutations model (PREMM1,2), a clinical prediction rule designed to be used by healthcare providers to estimate the probability that an individual carries a mutation in the MLH1 or MSH2 mismatch repair genes (Balmana et al. JAMA 2006). PREMM1,2 was developed and subsequently validated in over 2000 patients who were at elevated risk of Lynch Syndrome and undergoing genetic evaluation. Lynch Syndrome, also known as hereditary non- polyposis colorectal cancer (HNPCC), is the most common hereditary colon cancer syndrome, and also increases the risk for several extracolonic cancers. MLH1 and MSH2 mutations are the most common underlying cause. In a subset of families, mutations are found in a third mismatch repair gene, MSH6, and lead to a milder phenotype. Tumors in patients with Lynch syndrome demonstrate microsatellite instability (MSI) and can show loss of expression of the affected mismatch repair gene, which may be detected by immunohistochemical analysis (IHC). In addition to PREMM1,2, two other prediction models have recently been developed, and a variety of clinical guidelines are also available for the clinician as risk assessment tools. The performance characteristics of the available models and clinical guidelines have not been compared with another, nor is it known which approach, or combination of approaches, is the most cost-effective method of identifying and managing patients with Lynch Syndrome. As an expansion of our prior work, the aims of this project are (1) To validate PREMM1,2 in several existing U.S. and international colon cancer registries, including the Colon Cancer Family Registries (CCFR), EPICOLON, and Ohio State cohorts;(2)To expand the PREMM1, 2 model to include prediction of MSH6 mutation carriers;(3) To develop a version of the PREMMM1,2,6 model that (i) allows for the incorporation of information on MSI and IHC for further refinement of the predicted probabilities of a germline mutation, and (ii) makes gene-specific predictions based on clinical history, MSI and IHC results;(4)To compare the PREMMM1,2,6 , Barnetson, MMRPro models in (i) their ability to distinguish mutation carriers from non-carriers;(ii) different settings (population or clinic-based cases);(iii) a population-based series of endometrial cancer cases;and (5) To perform a cost-effectiveness analysis to define the role of the PREMM1,2,6 model and other clinical and molecular strategies for identification of individuals at risk of Lynch syndrome. PUBLIC HEALTH RELEVANCE: The results of this effort will achieve several goals of PA-07-021. It will (i) lead to a comprehensive clinical and public health approach to the identification and management of patients with hereditary colon cancer;(ii) allow for more precise estimation of the specific tumors associated with each MMR gene and therefore more targeted cancer screening and prevention approaches;and (iii) bring together investigators from diverse backgrounds, including geneticists, molecular epidemiologists, statisticians and clinicians, who will work together, share existing data and expertise to address research questions that could not be answered in isolation.